Autosomal dominant polycystic kidney disease (ADPKD) affects about 1/1000 people and is a common cause of end-stage renal disease (about 4% of the total US ESRD population). Although the renal manifestations are the most recognized clinical features of this disorder, it is a systemic disease associated with a number of other important clinical problems: hypertension that predates the renal insufficiency (about 70%), hepatic cysts (about 40%), cerebral aneurysms (about 7%), cardiac valvular abnormalities and aortic aneurysms. ADPKD describes a group of at least three genetically distinct disorders. Although the chromosome 4-linked form of the disease (PKD2) may be somewhat milder than the more common chromosome 16-linked disease (PKD1), the three forms of the disease are essentially phenotypically identical. Investigators have hypothesized that these diseases may develop as a consequence of defects in interactive factors involved in a common pathway. Our recent report describing the complete sequence of the PKD1 gene provides further evidence in support of this model. We have determined that the PKD1 gene product is likely to be a membrane glycoprotein with a large extracellular domain, multiple membrane spanning regions, and a cytoplasmic COOH end. The extracellular domain includes two leucine rich repeats (LRR) with flanking cysteine clusters, a motif that is known to be involved in mediating protein-protein interactions. We have hypothesized that the protein is likely to be involved in transducing "information" from the extracellular environment to the cytoplasm and thus likely to be involved in intracellular signaling. We propose to use a number of complementary strategies to identify the extracellular and intracellular protein binding partners for PKD 1. The critical residues of the binding site will be further characterized using a novel approach previously developed by us. Identification of the binding partners for PKD 1 will not only greatly improve our understanding of the pathophysiology of this disorder but may yield important therapeutic tools that can be used to alter the course of the disease.